Lack of biomarkers makes it tough to target Parkinson's

Large studies may provide some answers

After Alzheimer’s, Parkinson’s disease is the second most common neurodegenerative disorder in the United States, with roughly half a million Americans affected and 50,000 new cases reported each year.

It is primarily a disease of older age. The average age of onset is 60, though occasionally it appears much earlier. The cause is unknown, though many hypotheses involving genetic and environmental factors have been proposed. Its most common and usually first symptom is easier to discern: Trembling and shaking of a hand, foot, arm or leg that worsens with time. Other symptoms include slowed movement, a shuffling gait and stooped posture. Occasionally, there is depression, personality changes, dementia, speech impairments and insomnia.

Treatment is limited to symptoms, often drugs that affect or boost levels of dopamine, a neurotransmitter that helps brain cells communicate. There is no cure. Progress toward finding a cure has been slowed, in part, by the lack of biomarkers for the disease – indicators that scientists and doctors can use to diagnose Parkinson’s objectively, assess its progression and the efficacy of a treatment.

A $40 million, five-year study has just been launched to find these biomarkers – if they exist. The landmark observational clinical study, called the Parkinson’s Progression Markers Initiative (PPMI) and sponsored by The Michael J. Fox Foundation, will enroll 400 newly diagnosed Parkinson’s patients and 200 healthy age-matched controls at 18 sites across the country. The University of California San Diego School of Medicine is one of those sites and will seek 20 Parkinson’s patients and 10 controls.

We asked Dr. Douglas Galasko, a professor in the UCSD Department of Neurosciences and the Shiley-Marcos Alzheimer’s Disease Research Center, to talk about the search for Parkinson’s biomarkers.

Q: Biomarkers exist for other neurodegenerative disorders, such as Alzheimer’s disease. Why has it been so difficult to find them for Parkinson’s disease?

A: There are several factors. Regarding the science involved, the task may be more difficult in Parkinson’s because the brain pathology is less widely distributed than in Alzheimer’s. From a practical viewpoint, the search for Parkinson’s biomarkers began later than in Alzheimer’s disease, but the Parkinson’s field has made promising progress recently. Finally, scaling up efforts to have large numbers of patients studied in a uniform way is only now being applied to the quest for Parkinson’s biomarkers.

Q: How has the lack of a marker or markers hindered PD diagnosis, treatment and research?

A: For most patients with Parkinson’s disease, an experienced neurologist can make an accurate diagnosis. For patients who have unusual, mild or ambiguous findings, a biomarker could help to improve diagnostic accuracy. Most clinical trials for Parkinson’s involve medications to improve tremor and movement. Only a few drugs have been studied in efforts to slow down progression. For these types of drugs, biomarkers can provide a valuable readout of whether the drug is influencing the brain in a beneficial way – for example by measuring biomarkers of brain structure or chemistry. Finally, biomarkers could aid research by helping us to better understand how to measure the progression of Parkinson’s disease, how genetic and environmental risk factors affect the brain, and how to measure changes in Parkinson’s that precede the development of the typical movement disturbances of tremor, stiffness and slowing.

Q: What would constitute an ideal PD biomarker? Are there any current, likely candidates?

A: An ideal biomarker could detect changes related to Parkinson’s early in the course of the disease, and would sensitively measure change over time. It would be quick, convenient and inexpensive to obtain. Although a blood test in theory could meet these requirements, brain disorders in general don’t show up as changes in markers in the blood. So, we rely more on imaging the brain or analyzing the cerebrospinal fluid (which surrounds and bathes the brain and spinal cord). For Parkinson’s, a DATscan, available in Europe and recently approved by the FDA, is one such method. This is a single-photon emission computed tomography image, similar to a CAT scan, that’s taken after a radio-labeled tracer is injected into a vein, which provides a picture of circuits in the brain related to dopamine.

Another approach is to measure levels of a protein called alpha-synuclein, which builds up in the brain in Parkinson’s and in the cerebrospinal fluid. Studies from several centers in the United States and Germany have found that levels of alpha-synuclein can distinguish Parkinson’s from other types of brain problems. These and other biomarkers will be more extensively investigated in the PPMI study.

For more information about the PPMI at UCSD, contact Deborah Fontaine or Christina Gigliotti at 858-622-6301 or visit